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Sustained elevated intraocular pressures after intravitreal injection of anti-VEGF agentsElevated intraocular pressure (IOP) after an intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents for age-related macular degeneration (AMD) is not uncommon, but this study failed to identify any significant risk factors for its occurrence.

Studies investigating transient increases in intraocular pressure (IOP) measurements after intravitreal injection (IVI) of anti-VEGF agents have consistently shown that despite the rapid increase in IOP measurements at the time of the injection, normalization of IOP measurements takes place within the first 30 minutes to 60 minutes. The MARINA and ANCHOR trials revealed no sustained increases in IOP measurements with Lucentis (ranibizumab) treatment. The VISION and PA_CORES trials also failed to show any increases in IOP measurements with Macugen (pegaptanib) and Avastin (bevacizumab) treatments, respectively. However, recently, there have been several case reports (28 patients) of sustained elevated IOP measurements in eye receiving either Lucentis (9 cases) or Avastin (19 cases).

Methods & Results

A retrospective review of medical records identified a total of 127 patients (155 eyes) received an intravitreal injection of anti-vascular endothelial growth factor agents (bevacizumab, ranibizumab, or pegaptanib) ranging from 1 to 39 injections for more than a period of 30 to 1759 days. Among this population, 12 patients (14 eyes; 9.4%) developed elevated IOP >25 mmHg. Of these, 7 patients (5.5%) developed sustained elevated IOP (IOP >25 mmHg on 2 separate visits requiring glaucoma medication or surgery), of which 8 eyes required topical medications and 1 eye underwent glaucoma surgery. Mean IOP of injected eyes receiving intravitreal injection was 15.2 ± 2.4 mmHg, and the mean IOP was 14.9 ± 2.6 mmHg for noninjected eyes. Among eyes that had elevated IOPs, there was no association with injection frequency, number of injections, or anti-vascular endothelial growth factor agent used.

Transient increases in IOP measurements after the injection of anti-VEGF agents have been well described. However, recent studies have shown that pressure elevations can occur over a prolonged period. Interestingly, this phenomenon was not described in the initial large-scale studies of each individual anti-VEGF agent and although mechanisms such as low-grade inflammatory reactions, outflow tract occlusion, and other mechanisms have been proposed, the exact cause of the sustained elevated IOP measurements continues to be poorly understood.

The researchers analyzed the collective set of IOP measurements over a set period of 300 days to determine whether there was any pattern of change in IOP measurements correlating with the number of injections received during this time. They hypothesized that the increase in pressure should correlate with the number of injections. Based on the reletively flat slope of FIGURE 2, they did not observe any association between the frequency of injections an eye received and a change in IOP measurements. Additionally, as in FIGURE 3, there was no observed association between the number of injections and increase in IOP measurements among those who did not show a sustained elevation in IOP measurements. The researchers found no evidence that one can predict a tendency toward increasing measured IOP as one continues to administer IVIs. Thus, this study suggests that sustained elevated IOP measurements are independent of the frequency of injections and can occur after a single IVI and after as many as 39 injections. These findings argue against the recent theory that sustained elevated IOP measurements are being caused by outflow tract obstruction by high-molecular-weight protein aggregates found in injection packaging.

Some previous case reports have speculated that an increase in IOP may be more specific to either Lucentis or Avastin, while other studies have suggested that this can occur with either drug. This study supports this latter assertion but also brings to attention that sustained elevated IOP measurements can occur after intravitreal Macugen (pegaptanib) injection. To our knowledge, there has been no previously reported cases of sustained increased IOP measurements immediately after Macugen injections, although there have been a total of two reported cases of sustained pressure elevations in patients who initially had Macugen injections before switching to intravitreal Avastin and/or Lucentis injections. At this point, we have insufficient data to determine if the risk is different between these three anti-VEGF agents.

The current study of sustained elevated IOP measurements certainly confirms the reports of others that sustained elevated IOP measurements can occur after IVIs. However, the study does not support but cannot rule out any of the currently proposed explanations, which include low-grade inflammatory reactions not detectable by standard slit-lamp examination, direct drug toxicity to the physiologic functioning of the trabecular meshwork, and mechanical obstruction by injected materials in the trabecular meshwork. The etiology of this problem remains unknown, and we have to consider more idiosyncratic factors for its pathogenesis, including the unique genetic makeup of each patient.

In summary, elevated IOP, sustained or unsustained, after intravitreal injection is not uncommon. No association with patient demographics or injection history was identified in the authors' study population.